CD19 is a 95 kDa membrane receptor that is expressed early in B cell differentiation and continues to be expressed until the B cells are triggered to terminally differentiate (Pezzutto et al., (1987) J Immunol. 138:2793; Tedder et al. (1994) Immunol Today 15:437). The CD19 extracellular domain contains two C2-type immunoglobulin (IG)-like domains separated by a smaller potentially disulfide-linked domain. The CD19 cytoplasmic domain is structurally unique, but highly conserved between human, mouse, and guinea pig (Fujimoto et al, (1998) Semin Immunol. 10:267). CD19 is part of a protein complex found on the cell surface of B lymphocytes. The protein complex includes CD19, CD21 (complement receptor, type 2), CD81 (TAPA-1), and CD225 (Leu-13) (Fujimoto, supra).
CD19 is an important regulator of transmembrane signals in B cells. An increase or decrease in the cell surface density of CD19 affects B cell development and function, resulting in diseases such as autoimmunity or hypogammaglobulinemia (Fujimoto, supra). The CD19 complex potentiates the response of B cells to antigen in vivo through cross-linking of two separate signal transduction complexes found on B cell membranes. The two signal transduction complexes, associated with membrane IgM and CD19, activate phospholipase C (PLC) by different mechanisms. CD19 and B cell receptor cross-linking reduces the number of IgM molecules required to activate PLC (Fujimoto, supra; Ghetie, supra). Additionally, CD19 functions as a specialized adapter protein for the amplification of Arc family kinases (Hasegawa et al., (2001) J Immunol 167:3190).
CD19 binding has been shown to both enhance and inhibit B-cell activation and proliferation, depending on the amount of cross-linking that occurs (Tedder, supra). CD19 is expressed on greater than 90% of B-cell lymphomas and has been predicted to affect growth of lymphomas in vitro and in vivo (Ghetie, supra). Antibodies generated to CD19 have been murine antibodies. A disadvantage of using a murine antibody in treatment of human subjects is the human anti-mouse (HAMA) response on administration to the patient. Accordingly, the need exists for improved therapeutic antibodies against CD19 which are more effective for treating and/or preventing diseases mediated by CD19.